This six-site parallel R01 application requests funding for a three year study of the efficacy and safety of methylphenidate (MPH) in preschool children with Attention-Deficit/ Hyperactivity Disorder (ADHD). Although MPH's use in all age groups is increasing, its package insert prohibits its use in preschool children. Previous MPH preschool treatment studies have few subjects, and their results cannot be combined to yield needed safety information. The proposed study will address these concerns by mounting a six-site, controlled trial of 44 ADHD children per site, or 264 children total. It will be based at the New York State Psychiatric Institute (NYSPI), Duke University, Johns Hopkins University (JHU), New York University (NYU), University of California at Los Angeles (UCLA), and University of California at Irvine (UCI). Each site's subjects (N=44) will include: Group 1, ADHD preschoolers (n=33), ages 3-5 years, 6 months; and Group 2 (n=11), a contrast ADHD group, ages 6-8. After assessment, all children will enter a four-part study. Phase l will be a 3 week, open-label safety titration trial of MPH, 2.5 - 10 mg/dose, given 3 times daily (t.i.d.). Those without impairing side effects will enter Phase 2, a five week double-blind, placebo controlled, titration trial, with random assignments (weekly) to either placebo or to one of 4 doses of MPH (2.5, 5, 7.5, and 10 mg/dose) and monitored once in a laboratory (analog) classroom. Phase III will be an open-label, one-year extension, and Phase IV will be a double-blind, placebo discontinuation trial. Aim I is to determine the safety and efficacy of MPH in preschoolers with ADHD. Aim 2 is to test for differences between Groups 1 and 2 in dose-response to MPH. Aim 3 is to examine if two putative risk loci, the dopamine D4 receptor gene (DRD4) or the dopamine transporter gene (DATI), are associated with ADHD in a family-based association study of parent to child allele transmission, and whether dose response to MPH is related to generic variability at these two loci.